Acute lung injury and respiratory failure is a major cause of morbidity and mortality in combined smoke inhalation and burn injury, a lethal inflammatory condition accounting for more than 100,000 hospitalizations in the United States on an annual basis. Inotek Corporation is developing a unique anti-inflammatory compound, mercaptoethylguanidine (MEG), which interrupts multiple pathogenic mechanisms identified in smoke inhalation and burn injury induced acute lung injury: MEG 1) selectively inhibits inducible nitric oxide synthase (iNOS) activity, decreases iNOS mRNA translation, and accelerates iNOS degradation, 2) potently scavenges peroxynitrite, 3) inhibits pro-inflammatory cytokine expression (TNF-alpha and IL-1beta), and 4) inhibits expression of MIP-1alpha and MIP-2, thereby reducing leukocytic infiltration. Inotek has obtained preliminary data showing that MEG markedly reduces lymph flow, increases oxygenation, and reduces fluid accumulation in a clinically- relevant ovine model of combined smoke inhalation and burn injury. The specific aim of this proposal is to establish the pharmacodynamic and pharmacokinetic profile of MEG in this large animal model in order to confirm efficacy and provide a rationale foundation for selection of clinical dosing regimens. The proposed scope of work will justify Phase II SBIR funding to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA, and a Phase 1 clinical trial. PROPOSED COMMERCIAL APPLICATIONS: The annual domestic impact of burn injury and smoke inhalation induced acute lung injury on the health care market is estimated at > $50 million. The worldwide market (developed countries only) is four times larger. Given the absence of a specific, safe, and convenient existing therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high sustained price point ($1000 per patient). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $250 million (annual).